This invention relates to a novel process for the prevention of chlorinated by-products in the production of N-acetyl-para-aminophenol (APAP) by the Beckmann rearrangement of 4-hydroxyacetophenone oxime using thionyl chloride as the catalyst.
U.S. Pat. No. 4,524,217, the entire disclosure of which is herein incorporated by reference, describes a novel process for the preparation of N-acyl-hydroxy aromatic amines in general and specifically N-acetyl-para-aminophenol (APAP), by reacting a hydroxy aromatic ketone such as 4-hydroxyacetophenone with a hydroxylamine salt and a base to obtain the ketoxime of the ketone, e.g., 4-hydroxyacetophenone (4-HAP) oxime and then subjecting the oxime to a Beckmann rearrangement in the presence of a catalyst to form said N-acyl-hydroxy aromatic amines. Thionyl chloride in liquid sulfur dioxide is disclosed as a catalyst.
U.S. patent application Ser. No. 118,117, filed Nov. 6, 1987, discloses and claims a process of carrying out the Beckmann rearrangement of 4-HAP oxime to APAP utilizing thionyl chloride as a catalyst in liquid sulfur dioxide as solvent, wherein an inorganic iodide, e.g., potassium iodide is added to minimize the formation of chlorinated by-products.
Pending Fruchey et al. U.S. patent application Ser. No. 217,652 filed July 12, discloses and claims the use of an alkyl alkanoate as solvent for the thionyl chloride catalyst in carrying out the Beckmann rearrangement of 4-HAP oxime to APAP. Also disclosed and claimed is the addition of an alkali metal iodide such as potassium iodide to the reaction to minimize the formation of undesirable by-products. The entire disclosure of this application is incorporated by reference.
Although the process for the production of APAP as set forth in U.S. Pat. No. 4,524,217 is very effective, it has been found that a certain chlorinated by-product is formed during the Beckmann rearrangement of the 4-hydroxyacetophenone oxime when using said thionyl chloride as the Beckmann rearrangement catalyst. The chlorinated by-product which is formed during said Beckmann rearrangement is 3-chloro-4-hydroxyacetanilide (CAPAP). CAPAP is merely APAP chlorinated in the 3 position and although the exact mechanism for its formation has not yet been determined, it was discovered as a trace impurity in the crude APAP from the Beckmann reactor and also in the final product.
Although the 3-chloro-4-hydroxyacetanilide which is formed during the Beckmann rearrangement of 4-hydroxyacetophenone oxime when using thionyl chloride as catalyst is not known to have any detrimental effects, there is some indication that 3-chloro-4-hydroxyacetanilide affects the color of the APAP over a period of time. Nevertheless, experiments are inconclusive and are affected by the manner in which APAP is purified, either a single or double crystallization, etc. However, as can well be appreciated by those skilled in the art, APAP is an important commodity of commerce being one of the most widely used over-the-counter analgesics. It goes without saying that for human consumption, this product should be as pure as possible and chlorinated by-products are definitely not desirable.